Modulation of a patient's immune system using immunotherapeutic approaches has shown remarkable success against hematological neoplasms and some solid tumors, including metastatic melanoma and colorectal carcinoma. In contrast to these successes, solid tumors, including glioblastoma (GBM) tumors have not yet responded to immunotherapy approaches. This is largely due to the fact that many solid tumors and the microenvironments that they create are highly immunosuppressive and tumor promoting, supporting tumor growth and preventing the localization and functions of cytotoxic immune cells. Therefore, an approach to overcome the influence of the tumor microenvironment (TME) and the impact on infiltrating immune cells that are responsible for the elimination of transformed cells is required as a first step in developing successful immunotherapies for GBM and other solid tumors.
For example, while childhood leukemias have shown remarkable responses to T cell-based therapeutics; treatment of solid tumors has not been nearly as successful. Along with a lack of tumor-specific antigens, the immunosuppressive microenvironment of many solid tumors has thus far been an insurmountable barrier, precluding CAR T-cell immunotherapy. Brain tumors, which represent 20% of childhood cancers, are highly infiltrated by myeloid cells that render the tumor highly resistant to the cytotoxic functions.
As such, an approach to overcome the influence of the tumor microenvironment (TME) and the impact on infiltrating immune cells that are responsible for the elimination of transformed cells is strongly needed as a first step in developing successful immunotherapies for GBM and other solid tumors.
Glioblastoma (GBM), a WHO grade IV astrocytoma, is the most aggressive primary brain tumor in adults and children, with a 5 year survival rate of <10% and 40%, respectively (Omuro A, DeAngelis L M. Glioblastoma and other malignant gliomas: a clinical review. JAMA 2013; 310:1842-1850; included by reference in its entirety herein). Standard therapy for patients with GBM includes surgery, temozolomide chemotherapy, and radiation, and provides only a modest extension of survival. For many patients, treatment associated side effects preclude a reasonable quality of life. Adoptive cellular immunotherapies are appealing for patients with GBM because these cells have the potential to efficiently home to the tumor site and specifically target tumor cells, without injury to neural and glial structures (Choi B D, Pastan I, Bigner D D et al. A novel bispecific antibody recruits T cells to eradicate tumors in the “immunologically privileged” central nervous system. Oncoimmunology 2013; 2:e23639; Grupp S A, Kalos M, Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368:1509-1518; Miao H, Choi B D, Suryadevara C M et al. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS One 2014; 9:e94281; Ransohoff R M, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 2012; 12:623-635; all incorporated by reference in their entireties herein). Like many types of solid tumors found in a variety of tissues, GBM tumor cells create a complex tumor microenvironment (TME) that includes regulatory T cells (Tregs), myeloid derived suppressor cells (MDSCs), and tumor associated macrophages (TAMs) that prevent immune surveillance by endogenous T cells and natural killer (NK) cells, reduce antigen presentation, and hinder the activity of adoptively transferred anti-tumor T cells (Razavi S M, Lee K E, Jin B E et al. Immune Evasion Strategies of Glioblastoma. Front Surg 2016; 3:11; Kostianovsky A M, Maier L M, Anderson R C et al. Astrocytic regulation of human monocytic/microglial activation. J Immunol 2008; 181:5425-5432; Beavis P A, Slaney C Y, Kershaw M H et al. Reprogramming the tumor microenvironment to enhance adoptive cellular therapy. Semin Immunol 2016; 28:64-72; all incorporated by reference in their entireties herein). Novel treatments that circumvent this suppressive milieu could greatly improve the endogenous anti-tumor response for patients harboring GBM or other types of solid tumors, as well as enhance the efficacy of immunotherapies, such as antibody-mediated checkpoint blockade, antibody-induced cytotoxicity, and engineered T cell therapies.
In spite of the successes against hematologic malignancies, immunotherapeutic interventions for glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. Accordingly, new approaches to modify a tumor microenvironment (TME) in a subject in need are needed.